Compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders

Patent metadata

Field	Value
Publication number	US-10179771-B2
Application number	US-201615262097-A
Country	US
Kind code	B2
Filing date	Sep 12, 2016
Priority date	Jan 23, 2014
Publication date	Jan 15, 2019
Grant date	Jan 15, 2019

Abstract

Novel benzimidazoles according to Formula I, able to inhibit JAK are disclosed, these compounds may be prepared as a pharmaceutical composition, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, allergic diseases, inflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 or hypersecretion of interferons.

First claim

The invention claimed is:

1. A compound according to Formula I:

wherein
R 1 is H, or Me;
L 1 is —NR 2 —; —O—, or —CH 2 —;
Cy is phenyl;
R 2 is H, or C 1-4 alkyl;
R 3 is H, halo, C 1-4 alkyl optionally substituted with one or more halo, or C 1-4 alkoxy optionally substituted with one or more halo;
R 4 is H, or halo;
R 5 is —CN, halo, or is -L 2 -R 6 ;
-L 2 is absent, or is —C(═O)—, —C(═O)NR 7 —, —NR 7 C(═O)—, —SO 2 NR 7 —, or —NR 7 SO 2 —;
R 6 is H, or C 1-6 alkyl optionally substituted with one or more independently selected R 8 groups;
R 7 is H, or C 1-4 alkyl;
R 8 is OH, CN, halo, or C 1-4 alkoxy,
L a is absent, or is —C(═O)—, —C(═O)O—, or —C(═O)NH—;
R a is:
H,
C 1-4 alkyl optionally substituted with one or more independently selected R b , or
C 3-7 monocyclic cycloalkyl optionally substituted with one or more independently selected R c ,

R b is
halo,
CN,
OH,
C 1-4 alkoxy,
C 3-7 cycloalkyl,
—SO 2 —C 1-4 alkyl, or
—C(═O)NR b1 R b2

R c is
halo,
CN,
OH,
C 1-4 alkyl,
—C(═O)OH, or
—C(═O)NR c1 R c2 ; and
each R b1 , R b2 , R c1 and R c2 is independently selected from H, and C 1-4 alkyl, or a pharmaceutically acceptable salt thereof.

2. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is Me.

3. A compound or pharmaceutically acceptable salt according to claim 1 , wherein the compound is according to Formula IIa:

wherein L 1 , R 3 , R 4 , L a , R a and R 5 are as described in claim 1 .

4. A compound or pharmaceutically acceptable salt according to claim 1 , wherein the compound is according to Formula IVa or IVd:

wherein R 3 , R 4 , R 5 , L a , and R a are as described in claim 1 .

5. A compound or pharmaceutically acceptable salt according to claim 1 , wherein the compound is according to Formula Va or Vd:

wherein R 3 , R 4 , R 5 , L a , and R a are as described in claim 1 .

6. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 4 is H, F, or Cl.

7. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is H, Me, or Et.

8. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 5 is CN, F, Cl, —SO 2 Me or —SO 2 Et.

9. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R a is:

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to claim 1 .

11. A compound, or pharmaceutically acceptable salt thereof, according to claim 1 wherein the compound is:
N-(6-((4-cyano-2-ethyl-6-fluorophenyl)(methyl)amino)-1-methyl-1H-benzo[d]imidazol-4-yl)cyclopropanecarboxamide,
Methyl 6-((4-cyano-2-ethyl-6-fluorophenyl)(methyl)amino)-1-methyl-1H-benzo[d]imidazol-4-ylcarbamate,
N-(6-((4-cyano-2-ethyl-6-fluorophenyl)(methyl)amino)-1-methyl-1H-benzo[d]imidazol-4-yl)-2-fluorocyclopropanecarboxamide,
(1R,2R)-N-[6-(4-cyano-2-ethyl-phenoxy)-1-methyl-benzimidazol-4-yl]-2-fluoro-cyclopropanecarboxamide,
(1R,2R)-N-[6-(2-chloro-4-cyano-6-fluoro-N-methyl-anilino)-1-methyl-benzimidazol-4-yl]-2-fluoro-cyclopropanecarboxamide,
(1R,2R)-N-[6-(4-cyano-2-fluoro-N-methyl-anilino)-1-methyl-benzimidazol-4-yl]-2-fluoro-cyclopropanecarboxamide,
(1R,2R)-2-fluoro-N-[6-(2-fluoro-N,6-dimethyl-4-methyl sulfonyl-anilino)-1-methyl-benzimidazol-4-yl]cyclopropanecarboxamide,
(1R,2R)-2-fluoro-N-[6-(2-fluoro-N-methyl-4-methylsulfonyl-anilino)-1-methyl-benzimidazol-4-yl]cyclopropanecarboxamide,
N-[6-(2-fluoro-N,6-dimethyl-4-methylsulfonyl-anilino)-1-methyl-benzimidazol-4-yl]cyclopropanecarboxamide,
(1R,2R)-N-[6-(N,2-dimethyl-4-methylsulfonyl-anilino)-1-methyl-benzimidazol-4-yl]-2-fluoro-cyclopropanecarboxamide,
(1R,2R)-N-[6-(4-ethylsulfonyl-N,2-dimethyl-anilino)-1-methyl-benzimidazol-4-yl]-2-fluoro-cyclopropanecarboxamide, or
N-[6-[4-(cyanomethyl)anilino]-1-methyl-benzimidazol-4-yl]cyclopropanecarboxamide.

Assignees

• Menet Christel Jeanne Marie
• Mammoliti Oscar
• Blanc Javier
• Orsulic Mislav
• Roscic Maja
• Galapagos Nv

Inventors

• Menet Christel Jeanne Marie
• Mammoliti Oscar
• Blanc Javier
• Orsulic Mislav
• Roscic Maja

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title